Navarro V M, Fernández-Fernández R, Castellano J M, Roa J, Mayen A, Barreiro M L, Gaytan F, Aguilar E, Pinilla L, Dieguez C, Tena-Sempere M
Department of Cell Biology, Physiology and Immunology, University of Córdoba, 14004 Córdoba, Spain.
J Physiol. 2004 Dec 1;561(Pt 2):379-86. doi: 10.1113/jphysiol.2004.072298. Epub 2004 Oct 14.
The awakening of the gonadotrophic axis at puberty is the end-point of a complex cascade of sex developmental events that leads to the attainment of reproductive capacity. Recently, loss-of-function mutations of the gene encoding GPR54, the putative receptor for the KiSS-1-derived peptide metastin, have been linked to hypogonadotrophic hypogonadism, both in rodents and humans. However, the actual role of the KiSS-1/GPR54 system in the timing of puberty onset remains unexplored. We report herein that chronic central administration of KiSS-1 peptide to immature female rats induced the precocious activation of the gonadotrophic axis, as estimated by advanced vaginal opening, elevated uterus weight, and increased serum levels of luteinizing hormone (LH) and oestrogen. The central effect of KiSS-1 upon LH release appeared to be mediated via the hypothalamic LH-releasing hormone. In contrast, despite the well-documented permissive role of body fat stores and the adipocyte-derived hormone leptin in puberty maturation, acute activation of the gonadotrophic axis by KiSS-1 was persistently observed in pubertal animals under food deprivation, after central immunoneutralization of leptin, and in a model of leptin resistance. Overall, the present results, together with our recent data on maximum expression of KiSS-1 and GPR54 genes in the hypothalamus at puberty, provide novel evidence for a role of the KiSS-1 system as a downstream element in the hypothalamic network triggering the onset of puberty.
青春期促性腺轴的觉醒是一系列复杂的性发育事件的终点，这些事件最终导致生殖能力的获得。最近，编码GPR54的基因（推测为KiSS-1衍生肽metastin的受体）的功能丧失突变，在啮齿动物和人类中均与低促性腺激素性性腺功能减退有关。然而，KiSS-1/GPR54系统在青春期启动时间方面的实际作用仍未得到探索。我们在此报告，对未成熟雌性大鼠长期进行中枢给予KiSS-1肽，可诱导促性腺轴的早熟激活，这可通过提前出现阴道开口、子宫重量增加以及血清促黄体生成素（LH）和雌激素水平升高来估计。KiSS-1对LH释放的中枢作用似乎是通过下丘脑促性腺激素释放激素介导的。相比之下，尽管身体脂肪储存和脂肪细胞衍生激素瘦素在青春期成熟中具有公认的允许作用，但在食物剥夺的青春期动物中，在对瘦素进行中枢免疫中和后以及在瘦素抵抗模型中，仍持续观察到KiSS-1对促性腺轴的急性激活。总体而言，本研究结果与我们最近关于青春期下丘脑KiSS-1和GPR54基因最大表达的数据一起，为KiSS-1系统作为下丘脑网络中触发青春期开始的下游元件的作用提供了新证据。
